دورية أكاديمية
CYP2D6 Activity Is Correlated with Changes in Plasma Concentrations of Taurocholic Acid during Pregnancy and Postpartum in CYP2D6 Extensive Metabolizers.
| العنوان: | CYP2D6 Activity Is Correlated with Changes in Plasma Concentrations of Taurocholic Acid during Pregnancy and Postpartum in CYP2D6 Extensive Metabolizers. |
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| المؤلفون: | Czuba LC; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Malhotra K; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Enthoven L; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Fay EE; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Moreni SL; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Mao J; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Shi Y; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Huang W; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Totah RA; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Isoherranen N; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington., Hebert MF; Department of Pharmaceutics, School of Pharmacy (L.C.C., W.H., N.I.), Department of Pharmacy, School of Pharmacy (K.M., L.E., M.F.H.), Department of Obstetrics and Gynecology, School of Medicine (E.E.F., S.L.M., J.M., M.F.H.), and Department of Medicinal Chemistry, School of Pharmacy (Y.S., R.A.T.), University of Washington, Seattle, Washington mhebert@uw.edu. |
| المصدر: | Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Nov; Vol. 51 (11), pp. 1474-1482. Date of Electronic Publication: 2023 Aug 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics, etc.] Country of Publication: United States NLM ID: 9421550 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-009X (Electronic) Linking ISSN: 00909556 NLM ISO Abbreviation: Drug Metab Dispos Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Bethesda, Md., etc., American Society for Pharmacology and Experimental Therapeutics, etc.] |
| مواضيع طبية MeSH: | Cytochrome P-450 CYP2D6*/metabolism , Dextromethorphan*/metabolism, Humans ; Female ; Pregnancy ; Dextrorphan ; Taurocholic Acid ; Postpartum Period |
| مستخلص: | Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of >20% of marketed drugs. CYP2D6 expression and activity exhibit high interindividual variability and is induced during pregnancy. The farnesoid X receptor (FXR) is a transcriptional regulator of CYP2D6 that is activated by bile acids. In pregnancy, elevated plasma bile acid concentrations are associated with maternal and fetal risks. However, modest changes in bile acid concentrations may occur during healthy pregnancy, thereby altering FXR signaling. A previous study demonstrated that hepatic tissue concentrations of bile acids positively correlated with the hepatic mRNA expression of CYP2D6. This study sought to characterize the plasma bile acid metabolome in healthy women ( n = 47) during midpregnancy (25-28 weeks gestation) and ≥3 months postpartum and to determine if plasma bile acids correlate with CYP2D6 activity. It is hypothesized that during pregnancy, plasma bile acids would favor less hydrophobic bile acids (cholic acid vs. chenodeoxycholic acid) and that plasma concentrations of cholic acid and its conjugates would positively correlate with the urinary ratio of dextrorphan/dextromethorphan. At 25-28 weeks gestation, taurine-conjugated bile acids comprised 23% of the quantified serum bile acids compared with 7% ≥3 months postpartum. Taurocholic acid positively associated with the urinary ratio of dextrorphan/dextromethorphan, a biomarker of CYP2D6 activity. Collectively, these results confirm that the bile acid plasma metabolome differs between pregnancy and postpartum and provide evidence that taurocholic acid may impact CYP2D6 activity during pregnancy. SIGNIFICANCE STATEMENT: Bile acid homeostasis is altered in pregnancy, and plasma concentrations of taurocholic acid positively correlate with CYP2D6 activity. Differences between plasma and/or tissue concentrations of farnesoid X receptor ligands such as bile acids may contribute to the high interindividual variability in CYP2D6 expression and activity. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.) |
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| معلومات مُعتمدة: | P30 DK017047 United States DK NIDDK NIH HHS; R01 GM124264 United States GM NIGMS NIH HHS; T32 DK007247 United States DK NIDDK NIH HHS |
| المشرفين على المادة: | EC 1.14.14.1 (Cytochrome P-450 CYP2D6) 7355X3ROTS (Dextromethorphan) 04B7QNO9WS (Dextrorphan) 5E090O0G3Z (Taurocholic Acid) |
| تواريخ الأحداث: | Date Created: 20230807 Date Completed: 20231102 Latest Revision: 20240918 |
| رمز التحديث: | 20240918 |
| مُعرف محوري في PubMed: | PMC10586507 |
| DOI: | 10.1124/dmd.123.001358 |
| PMID: | 37550070 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-009X |
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| DOI: | 10.1124/dmd.123.001358 |